1. Field of the Invention
The present invention relates to substituted pyrazolidinone compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for a variety of therapies, including treatment of preterm labor, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteoporosis and other destructive bone disease or disorders, and other diseases and disorders associated with the prostaglandin EP2 and/or EP4 receptors.
2. Background
Certain prostanoid receptors and modulators of those receptors have been reported. See generally Eicosanoids: From Biotechnology to Therapeutic Applications (Plenum Press, New York); Journal of Lipid Mediators and Cell Signalling 14: 83-87 (1996); The British Journal of Pharmacology, 112: 735-740 (1994); PCT applications WO 96/06822, WO 97/00863, WO 97/00864, and WO 96/03380; EP 752421; U.S. Pat. Nos. 6,211,197 4,211,876 and 3,873,566; and Bennett et al. J. Med. Chem., 19(5): 715-717 (1976).
Physiological action of prostaglandin E2 (PGE2) is reported to be mediated through interaction with the prostaglandin E receptor(s). Four subtypes of the prostaglandin EP receptor have been identified: EP1, EP2, EP3, and EP4. The prostaglandin EP2 receptor including the cloning thereof has been reported. See U.S. Pat. Nos. 5,605,814 and 5,759,789. Binding of PGE2 to the EP2 receptor protein has been reported to result in an increase in cAMP levels, which can cause smooth muscle relaxation. See U.S. Pat. No. 5,605,814. Binding of PGE2 to the EP4 receptor also causes increases in cAMP levels leading to smooth muscle relaxation.
It also has been reported that genetic deletion of the EP2 receptor indicates a key role in normal female fertility and control of blood pressure. See Journal of Clinical Investigation, 103(ii):1539-1545 (1999).
It would be desirable to have new compounds and methods for treatment of diseases and disorders associated with the prostaglandin EP2 and/or EP4 receptors. It also would be desirable to have new compounds for treatment of diseases and disorders associated with inappropriate activation of the EP2 and/or EP4 receptors.